Synthetic studies toward biselides. Part 2: synthesis of the macrolactone part of biselides A and B using allylic oxidation

Synthesis of the macrolactone part of biselides A (1) and B (2), marine cytotoxic polyketides, was achieved by using regioselective allylic oxidation as a key step.     

Mass spectroscopy of natural products. VI—Localization of functional groups in the hopane skeleton

The mass spectral fragmentation of hopane derivatives with oxygenated substituents at C-3, C-6, C-7, C-15, C-16 and C-22 is discussed. It is shown, that the positions of functional groups in rings A and B or D and E respectively can be distinguished using several derivatives and deuterated analogues.     

Cal-B-catalyzed alkoxycarbonylation of a-ring stereoisomeric synthons of 1alpha,25-dihydroxyvitamin D3 and 1alpha,25-dihydroxy-19-nor-previtamin D3: a comparative study. first regioselective chemoenzymatic synthesis of 19-nor-A-ring carbonates

A comparative study of alkoxycarbonylation processes of both 19-nor-A-ring and A-ring stereoisomers of 1alpha,25-dihydroxyvitamin D3 analogues catalyzed by Candida antarctica lipase B (CAL-B) has been described. The presence of the methyl group in the A-ring at C-2, as in 3-6, has a determining role in the regioselectivity of the biocatalysis, mainly allowing the hydroxyl group at C-5 position to react. For the 19-nor-A-ring stereoisomers 7-10, which lack the C-2 methyl group, the configurations at C-3 and C-5 have a high influence in the selectivity exhibited by CAL-B. Thus, each couple of enantiomers showed opposing regioselectivities depending on the C-3 configuration. When C-3 possesses an (S)-configuration, enzymatic alkoxycarbonylations took place at the C-5-(R) or C-5-(S) hydroxyl groups. However, if the chiral centers at C-3 are (R), CAL-B alkoxycarbonylated the C-3-(R) hydroxyl group independently of the configuration at C-5. The corresponding carbonates are useful A-ring precursors of 1alpha,25-dihydroxyvitamin D3 analogues, selectively modified at the C-1 or C-3 positions. In addition, an improved synthesis of cis A-ring synthons 5 and 6 is described using a Mitsunobu methodology.     

Unexpected B-ring regioselective di-nitration of diosmetin, a Citrus flavonoid

Nitration in position C-8 of diosmetin, an easily available citroflavonoid, was studied in order to gain access to original analogs. The one-step nitration proved impossible, as mono or di-nitration on C-2′ and C-6′ positions on the lateral B ring of the molecule was exclusively observed. This surprisingly straightforward di-nitration of ring B, showing a lack of reactivity of ring A despite its high activation, has never been mentioned to date. Nitration in position C-8 was therefore performed in five steps, requiring selective deactivation of ring B.     

Daphnogirins A and B, two biflavones from Daphne giraldii

Two new biflavonoids, daphnogirins A (1) and B (2), were obtained from the roots of Daphne giraldii. Their structures were established on the basis of the spectral data and X-ray diffraction data of the co-crystal of 1 and 2. Daphnogrins A and B have the same configuration at C-1 and opposite configurations at C-16 and C-17. Oxygen radical scavenging assay has indicated that they are of significant antioxidative activity.     

Trichilin B, a novel limonoid with highly rearranged ring system from Trichilia connaroides

Trichilin B (2), a limonoid having an unprecedented highly rearranged ring system, along with biosynthetically correlated trichilin A (1), was isolated from Trichilia connaroides. The structures were elucidated by spectroscopic analysis. Compound 2 features a unique 9,17-oxygen bridge, while two unprecedented δ-lactone rings fused to rings A and B at C-5, C-9 and ring C at C-8, C-14. Their cytotoxic activities were also evaluated.     

Density functional theory and surface-enhanced Raman spectroscopy studies on endocrine-disrupting chemical,dimethyl phthalate

A method to monitor endocrine-disrupting chemical contamination phthalate esters (PAEs) by surface-enhanced Raman scattering (SERS) spectroscopy has been investigated. The molecular structure and assignment of the vibrations of dimethyl phthalate (DMP), forming short chains in PAEs, has been studied by density functional theory (DFT) calculations. The structure of DMP with the dihedral angles of 1C-6C-11C-13O and 4C-5C-18C-20O being 133.78° and −24.00°, respectively, has the lowest energy. Theoretical vibrational frequencies using B3LYP/6-31 + G(d) (after scaling) show excellent agreement with the experimental normal Raman spectrum. In the region 200–1800 cm⁻¹, SERS spectra of DMP were measured using ordered gold nanosubstrates. All except the weak signals in the normal Raman spectrum of DMP were successfully enhanced. These results demonstrate that SERS technology could be developed as a rapid method for screening of DMP.     

Diastereoselective reactions at enantiomerically pure, sterically congested cyclohexanes as an entry to wailupemycins A and B: total synthesis of (+)-wailupemycin B

Wailupemycin A (1) and B (2) are polyketide natural products with a highly substituted cyclohexanone core. Three different routes for the syntheses of these compounds were pursued, which commenced from either (R)-(-)-carvone (ent-5) or (S)-(+)-carvone (5). In the first approach it was attempted to construct the skeleton of wailupemycin A from triol 19 (nine steps from ent-5; 19 % yield) by a sequence of diastereoselective epoxidation, nucleophilic ring opening at C-13 and carbonyl addition at C-5. The synthetic plan failed at the stage of the carbonyl addition to aldehyde 27, which had been obtained in seven steps (18 % yield) from triol 19. The second route included an epoxide ring opening at C-13 and a carbonyl addition at C-7 as key steps. It could have led to either wailupemycin A or B depending on the diastereoselectivity of the addition step. Starting from allylic alcohol 30 (six steps from ent-5; 59 % yield) the cyclohexanone 28 was obtained in five steps (54 % yield). Unfortunately, the carbonyl addition failed also in this instance. In the eventually successful third attempt the skeleton of wailupemycin B was built from cyclohexanone 43 (eight steps from 5; 53 % yield) by highly diastereoselective carbonyl addition reactions at C-7 and C-12. The phenyl group at C-14 was introduced at a late stage of the synthetic sequence. Careful protecting group manipulation finally allowed for the total synthesis of (+)-wailupemycin B. The absolute and relative configuration of the natural product was unambiguously confirmed. The total yield of wailupemycin B amounted to 6 % over 23 steps starting from (S)-(+)-carvone (5).     

Regioselective enzymatic acylations of polyhydroxylated eudesmanes: semisynthesis, theoretical calculations, and biotransformation of cyclic sulfites

Different lipase enzymes have been tested in order to perform regioselective acetylations on the eudesmane tetrol from vulgarin. High yields (95%) of 1,12-diacetoxy derivative (4) were achieved in 1 h with Candida antarctica lipase (CAL). However, only the 12-acetyl derivative (6) was obtained in similar yield with Mucor miehei (MML) or Candida cylindracea (CCL) lipases. The enzymatic protection at C-1 and C-12 has been used to form eudesmane cyclic-sulfites between C-6 and C-4 atoms. The R/S-sulfur configuration has been assigned by means of the experimental and theoretical (13)C and (1)H NMR chemical shifts. The theoretical shifts were calculated using the GIAO method, with a MM+ geometry optimization followed by a single-point calculation at the B3LYP/6-31G(*) level (B3LYP/6-31G(*)//MM+). Moreover, B3LYP/6-31G(*) geometry optimizations were carried out to test the B3LYP/6-31G(*)//MM+ results, for the deacetylated sulfites (12 and 15). In addition to the delta(C) and delta(H) shifts, the (3)J(HH) coupling constants were also calculated and compared with the experimental values when available. Finally, different reactivities have been checked in both sulfites by biotransformation with Rhizopus nigricans. While the R-sulfite gave 2 alpha- and 11 beta-hydroxylated metabolites, the S-sulfite yielded only regioselective deacetylations. Furthermore, both sulfites showed different reactivities in redox processes.     

Isolation, structural elucidation, and biosynthesis of 15-norlankamycin derivatives produced by a type-II thioesterase disruptant of Streptomyces rochei

Lankamycin, a 14-membered macrolide antibiotic, contains a 3-hydroxy-2-butyl side chain at C-13. To analyze the function of lkmE, which encodes type-II thioesterase in the lankamycin cluster, we carried out a gene disruption experiment. Disruption of lkmE resulted in a 70% decrease of lankamycin production concomitant with an accumulation of novel lankamycin derivatives (LM-NS01A and LM-NS01B), in which the C-13 side chain is replaced by a 1-carboxyethyl group. The biosynthetic origin of 1-carboxyethyl group was confirmed by incorporation of deuterium in [3-²H]3-methyl-2-oxobutyrate into the C-14 position. These results indicate that the biosynthesis of LM-NS01A and LM-NS01B starts from isobutyryl CoA in place of (S)-2-methylbutyryl CoA and LkmE removes the aberrantly loaded starter unit and restores lankamycin production.     

Total synthesis of (+/-)-scopadulin.

The first total synthesis of (+/-)-scopadulin, an aphidicolane diterpene, is described. The core structure (A/B/C/D ring system) was constructed by an initial synthesis of the B/C/D ring system by our reported methods and a subsequent A ring cyclization by intramolecular aldol condensation. A highly stereoselective cyanation of the tetracyclic enone by Et2AlCN gave a trans-fused A/B ring system with a beta-cyanide at C-4. Stereoselective construction of a quaternary carbon at C-4 was achieved by alpha-alkylation of the cyano group and conversion of the sterically hindered cyano group to a methyl group via our novel reaction for conversion of primary aliphatic amines into alcohols. Finally, the total synthesis of (+/-)-scopadulin was accomplished by a highly chemo- and stereoselective methylation at C-16 and modification of the C-4 alpha-functionality. The stereoselectivity observed in the MeTi(O-i-Pr)3-mediated methylation for the generation of a tertiary axial alcohol at C-16 is extremely high.     

Genetically engineered synthesis and structural characterization of cobalt-precorrin 5A and -5B, two new intermediates on the anaerobic pathway to vitamin B12: definition of the roles of the CbiF and CbiG enzymes

Two new cobalt corrinoid intermediates, cobalt-precorrin 5A and cobalt-precorrin 5B, have been synthesized with the aid of overexpressed enzymes of the vitamin B(12) pathway of Salmonella entericaserovar typhimurium. These compounds were made in several regioselectively (13)C-labeled forms, and their structures have been established by multidimensional NMR spectroscopy. The addition of CbiF to the enzymes known to synthesize cobalt-precorrin 4 resulted in the formation of cobalt-precorrin 5A, and the inclusion of CbiG with CbiF produced cobalt-precorrin 5B, which has allowed us to define the role of these enzymes in the anaerobic biosynthetic pathway. CbiF is the C-11 methylase, and CbiG, an enzyme which shows homology with CobE of the aerobic pathway, is the gene product responsible for the opening of the ring A delta-lactone and extrusion of the "C(2)" unit. The discovery of these long-sought intermediates paves the way for defining the final stages of the anaerobic pathway. It is of considerable evolutionary interest that nature uses two distinct pathways to vitamin B(12), both conserved over several billion years and featuring completely different mechanisms for ring-contraction of the porphyrinoid to the corrinoid ring system. Thus the aerobic pathway utilizes molecular oxygen to trigger the events at C-20 leading to contraction and expulsion of the "C(2)" unit as acetic acid from a metal-free intermediate, whereas the anaerobic route features internal delivery of oxygen from a carboxylic acid terminus to C-20 followed by extrusion of the "C(2)" unit as acetaldehyde, using cobalt complexes as substrates.     

Microcionamides A and B, bioactive peptides from the philippine sponge Clathria (Thalysias) abietina

Microcionamides A (1) and B (2) have been isolated from the Philippine marine sponge Clathria (Thalysias) abietina. These new linear peptides are cyclized via a cystine moiety and have their C-terminus blocked by a 2-phenylethylenamine group. Their total structures, including absolute stereochemistry, were determined by a combination of spectral and chemical methods. Compound 1 was shown to slowly isomerize about the C-36/C-37 double bond when stored in DMSO. Microcionamides A (1) and B (2) exhibited significant cytotoxicity against the human breast tumor cells lines MCF-7 and SKBR-3 and displayed inhibitory activity against Mycobacterium tuberculosis H(37)Ra.     

Total synthesis of two novel 5,6,7,8-tetrahydroindolizine alkaloids, polygonatines A and B

The structures of polygonatines A and B, two simple but structurally novel alkaloids, have been substantiated by synthesis. Cyclisation of 4-(1H-pyrrol-1-yl)butanoic acid or its ethyl ester produced 6,7-dihydroindolizin-8(5H)-one , formylation of which at C-3 followed by reduction afforded polygonatine A . Acetylation of this alkaloid followed by displacement of the acetate with ethanol yielded polygonatine B , possibly via an azafulvenium cation.     

Eremophilane,bakkane, secoeremophilane,and secobakkane sesquiterpenoids from Ligularia virgaurea collected in China

Secobakkane B (C-6/C-7 cleaved secobakkane type aldehyde), secovirgaurenols B and C (C-8/C-9 cleaved secoeremophilane type), a 1β,10β-epoxyfuranoeremophilane, two 1β,10β-epoxyeremophilanolides, and fukinospirolide C (bakkane-type lactone), as well as 33 known compounds were isolated from three samples of Ligularia virgaurea collected in China. Two of the three analyzed samples were grouped in the neoadenostylone (N) type, and the rest, a mixture of the 6-hydroxyeuryopsyn (H) and cacalol (C) types, out of five chemotypes found in this species.     

Cipadonoid A, a novel limonoid with an unprecedented skeleton, from Cipadessa cinerasecns

Cipadonoid A ( 1), a novel limonoid with an unprecedented skeleton, was isolated from the leaves of Cipadessa cinerasecns. Its structure and relative configuration were determined by spectroscopic analysis and computer modeling. 1 represents a new type of limonoid, characterized by a rearranged tetrahydropyranyl ring B incorporating usually exocyclic C-30. A possible biosynthetic pathway of 1 was also proposed.     

利用薯蓣皂甙元完整骨架形式合成1α,25-二羟基维生素D3

首次利用薯蓣皂甙元的完整骨架经16步反应以7.6%的总收率合成了骨化三醇(1α,25-二羟基维生素D₃)的光化反应前体. 3-苄基保护的薯蓣皂甙元经还原开E/F环产生3,16,26-胆甾三醇-3-苄醚(5). 除去化合物5 C-16羟基后, 其C-26羟基经消除和羟基化反应转移到C-25位. 目标分子A/B环结构单元通过薯蓣皂甙元A/B环的官能团转化被构筑. 按照已知的光化反应, (1S,3R)-胆甾-5,7-二烯-1,3,25-三醇能被转化成为1α,25-二羟基维生素D₃.     

Zur lokalisierrung funktioneller gruppen mit hilfe der massenspektrometrie—IX : 17 β-hydroxy-androstan-3,6-dione, 3-hydroxy-androstan-6,17-dione und 3,17β-dihydroxy-androstan-6-one

Mass spectra of steroids with a 3β-configurated hydroxy-group and a keto-function in position 6 are characterized in the case of cis-connection of the A/B-ring system by a key ion at M-71, whereas if the rings A and B are trans-connected the production of a key ion of mass 139 is preferred. The substitution of the 3-hydroxy group by a keto-function alters the main fragmentation routes: In the case of cis-connection of the A/B-ringsystem a key ion corresponding to the loss of C-3 to C-7 is observed, while by trans-connection of the A/B-ringsystem C-1 and C-2 are lost as C₂H₅-radical.     

Unambiguous NMR spectral assignments of salvinorin A

The complete assignments of the (1)H and (13)C NMR spectra of the hallucinogenic neoclerodane diterpenoid salvinorin A were determined in three different NMR solvents using HSQC, HMBC and COSY. Solvent systems are described that allow the resolution of all (1)H signals. Virtual coupling was observed for the protons at C-2, C-3 and C-4 in the 600 MHz (1)H spectrum in CDCl(3). The complete assignments of the (1)H and (13)C NMR spectra of salvinorin B are also reported.     

Ternifolide A, a new diterpenoid possessing a rare macrolide motif from Isodon ternifolius

Ternifolide A (1), a new diterpenoid featuring a unique 10-membered lactone ring formed between C-6 and C-15, along with ternifolide B (2), a nor-diterpenoid, and ternifolide C (3) were isolated from the leaves of Isodon ternifolius. Both H-8 and H-9 being α-orientations in compound 1 were found for the first time. The absolute configurations of 1 and 3 were confirmed by X-ray diffraction study. Compounds 1 and 3 were evaluated for their cytotoxicity.